ZA200202603B - Alkylamino substituted bicyclic nitrogen heterocycles as inhibitors of p38 protein kinase. - Google Patents

Description

ALKYLAMINO SUBSTITUTED BICYCLIC NITROGEN HETEROCYCLES AS INHIBITORS OF P38 PROTEIN

KINASE

The present invention relates to bicyclic nitrogen heterocycles. More particularly, the invention is concerned with alkylamino-substituted dihydro- . pyrimido[4,5-d)pyrimidinone derivatives, a process for their manufacture, their use, pharmaceutical preparations containing them and a process for the manufacture of the pharmaceutical preprations. : Mitogen-activated protein kinases (MAP) are a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation. The kinases are activated by a variety of signals including nutritional and osmotic stress,

UV light, growth factors, endotoxin and inflammatory cytokines. One group of MAP . kinases is the p38 kinase group which includes various isoforms (e.g, p38, p39 and p38Y). The p38 kinases are responsible for phosphorylating and activating : transcription factors as well as other kinases, and are themselves activated by physical and chemical stress, pro-inflammatory cytokines and bacterial lipopolysaccharide.

More importantly, the products of the p38 phosphorylation have been shown to mediate the production of inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2. Each of these cytokines has been implicated in numerous disease states and conditions. For example, TNF-a is a cytokine produced primarily by activated monocytes and macrophages. Its excessive or unregulated production has been implicated as playing a causative role in the pathogenesis of rheunatoid arthritis. More recently, inhibition of TNF production has been shown to have broad application in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma.

TNF has also been implicated in viral infections, such as HIV, influenza virus, and herpes virus including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.

Similarly, IL-1 is produced by activated monocytes and macrophages, and plays a role in many pathophysiological responses including rheumatoid arthritis, fever and reduction of bone resorption. The inhibition of these cytokines by inhibition of the p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states.

The compounds of formula I and their aforementioned salts are inhibitors of protein kinases, and exhibit surprisingly effective activity against p38 in vivo. The compounds of formula I do not exhibit activity against the T-cell tyrosine kinase p561cK at levels below about 10 uM. The compounds can be used for the treatment of ) 15 diseases mediated by the pro-inflammatory cytokines such as TNF and IL-1. : As used herein: "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl, and the like. "Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 2-methyipropylene, pentylene, and the like. “Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g, ethenyl, propenyl, and the like. "Alkynyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g, ethynyl, propynyl, and the like.

"Cycloalkyl" refers to a saturated monovalent cyclic hydrocarbon radical of three to seven ring carbons.

The cycloalkyl may be optionally substituted independently with one, two, or three substituents selected from alkyl, optionally substituted phenyl, or -C(O)R (where R is hydrogen, alkyl, haloalkyl, amino, monsubstituted amino, disubstituted amino, hydroxy, alkoxy, or optionally - substituted phenyl). More specifically, the term cycloalkyl includes, for example, cyclopropyl, cyclohexyl, phenylcyclohexyl, 4-carboxycyclohexyl, 2-carboxamido- cyclohexyl, 2-dimethylaminocarbonyl- cyclohexyl, and the like. “Cycloalkenyl” means an unsaturated non-aromatic monovalent cyclic hydrocarbon radical of three to seven ring carbons.

Representative examples include cyclohexenyl and cyclopentenyl. "Cycloalkylalkyl" means a radical -R2RD where R2 is an alkylene group and RP is a cycloalkyl group as defined herein, e.g, cyclopropylmethyl, cyclohexylpropyl, 3- cyclohexyl-2-methylpropyl, and the like.

“Acyl” means the group —C(O)R’, where R’ is alkyl, haloalkyl, heteroalkyl, .

aryl, heteroaryl, aralkyl or heteroaralkyl.

"Alkoxy", "aryloxy", " aralkyloxy”, or "heteroaralkyloxy" means a radical -OR } where R is an alkyl, aryl, aralkyl, or heteroaralkyl respectively, as defined herein, e.g., methoxy, phenoxy, pyridin-2-ylmethyloxy, benzyloxy, and the like.

"Halo" or “Halogen,” means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.

"Haloalkyl" means alkyl substituted with one or more same or different halo atoms, e.g., -CH1Cl, -CF3, -CH,CF3, -CH7CCl3, and the like, and further includes those alkyl groups such as perfluoroalkyl in which all hydrogen atoms are replaced by fluorine atoms.

"Hydroxyalkyl" means an alkyl radical as defined herein, substituted with one or more, preferably one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group.

Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-

(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxy-butyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably

< WO 01/29041 PCT/EP00/10077 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl.

Accordingly, as used herein, the term “hydroxyalkyl” is used to define a subset of heteroalkyl groups. "Monosubstituted amino" means a radical -NHR where R is alkyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocyclyl, or heterocyclylalkyl, e.g., methylamino, ethylamino, phenylamino, benzylamino, and the like. "Disubstituted amino" means a radical -NRR' where R and R’ are, independently of each other, alkyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocyclyl, or heterocyclylalkyl, or R and R' together with the nitrogen atom to which they are attached form a heterocyclyl ring. Representative examples include, but are not limited to, dimethylamino, methylethylamino, di(1-methyl-ethyl)amino, piperazin- 1-yl, and the like. : 15 "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms which is substituted independently with one or more ] substituents, preferably one, two, or three substituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano, methylenedioxy, ethylenedioxy, cycloalkyl, optionally substituted phenyl, heteroaryl, haloalkoxy, optionally substituted phenoxy, heteroaryloxy, -COR (where R is alkyl or optionally substituted phenyl), -(CR'R”)5-

COOR (where n is an integer from 0 to 5, R’ and R” are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl) or «(CR'R”)p-

CONRARb (where n is an integer from 0 to 5, R’ and R” are independently hydrogen or alkyl, and Ra and RD are, independently of each other, hydrogen, alkyl, cycloalkyl or cycloalkylalkyl, or R* and rR together with the nitrogen atom to which they are attached form a heterocyclyl ring). More specifically the term aryl includes, but is not limited to, phenyl, 1-naphthyl, and 2-naphthyl, and the derivatives thereof. "Aralkyl" means a radical -R2RD where R2 is an alkylene group and Rbisan aryl group as defined herein, e.g., benzyl, phenylethyl, 3-(3-chlorophenyl)-2- methylpentyl, and the like. "Aralkenyl" means a radical -R2RP where R2 is an alkenylene group and Rbis an aryl group as defined herein, e.g., 3-phenyl-2-propenyl, and the like.

w “Arylheteroalkyl” means a radical -R2Rb where R2 is an heteroalkylene group and RV is an aryl group as defined herein, e.g., 2-hydroxy-2-phenylethyl, 2-hydroxy- 1-hydroxymethyl-2-phenylethyl, and the like. "Optionally substituted phenyl" means a phenyl ring which is optionally 5 substituted independently with one or more substituents, preferably one or two substituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano, methylenedioxy, ethylenedioxy, cycloalkyl, cycloalkylalkyl, -COR (where R is alkyl or optionally substituted phenyl, -(CR'R”),-COOR (where n is an integer from 0 to 5,

R’ and R” are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl), or ~(CR’R”),-CONR2Rb (where n is an integer from 0 to 5, R’ and

R” are independently hydrogen or alkyl, and R2 and Rb are, independently of each other, hydrogen, alkyl, cycloalkyl or cycloalkylalkyl, or R*and R® together with the nitrogen atom to which they are attached form a heterocyclyl ring). "Heteroaryl” means a monovalent monocyclic or bicyclic radical of 5 to 12 i ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring is optionally substituted independently with one or more substituents, preferably one or two substituents, selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano, cycloalkyl, cycloalkylalkyl, -COR (where R is alkyl or optionally substituted phenyl, -(CR'R”)p-COOR (where n is an integer from 0 to 5, R’ and R” are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl), or —(CR’R”)-CONR2RP (where n is an integer from 0 to 5, R’ and R” are independently hydrogen or alkyl, and R? and Rb are, independently of each other, hydrogen, alkyl, cycloalkyl or cycloalkylalkyl, or R®and

R® together with the nitrogen atom to which they are attached form a heterocyclyl ring). More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazoly, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazoly},

quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, and the derivatives thereof. "Heteroaralkyl" means a radical -R3RD where R2 is an alkylene group and RP is a heteroaryl group as defined herein, e.g., pyridin-3-ylmethyl, 3-(benzofuran-2- yl)propyl, and the like. "Heteroaralkenyl" means a radical -R2RD where R2 is an alkenylene group and

Rb is a heteroaryl group as defined herein, e.g., 3-(pyridin-3-yl)propen-2-yl, and the . like. "Heterocyclyl" means a saturated or unsaturated non-aromatic cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from

NR (where R is independently hydrogen or alkyl), O, or S(O), (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group. The heterocyclyl ring may be optionally } substituted independently with one, two, or three substituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, monosubstituted amino, disubstituted amino, -COR (where R is alkyl or optionally substituted phenyl), -(CR'R”),,-COOR (n is an integer from 0 to 5, R’ and R” are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl), or -(CR’R”),-CONR2RD (where n is an integer from 0 to 5, R’ and R” are independently hydrogen or alkyl, and R2 and RD are, independently of each other, hydrogen, alkyl, cycloalkyl or cycloalkylalkyl, or R* and R® together with the nitrogen atom to which they are attached form a heterocyclyl ring). More specifically the term heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidino, N- methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl, 3-pyrrolidino, morpholino, thiomorpholino, thiomorpholino- 1- oxide, thiomorpholino-1,1- dioxide, pyrrolinyl, imidazolinyl, and the derivatives thereof. "Heterocyclylalkyl" means a radical -R28RP where R2 is an alkylene group and

Rb is a heterocyclyl group as defined herein, e.g., tetrahydropyran-2-ylmethyl, 4- methylpiperazin- 1-ylethyl, 3-piperidinylmethyl, and the like. “Heteroalkyl” means an alkyl radical as defined herein with one, two or three substituents independently selected from -OR®, -NR®RS, and -S(0)pR? (where n is an

% integer from 0 to 2 ). R*is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl, aryloxycarbonyl, carboxamido, or mono- or di-alkylcarbamoyl. R® is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl. Ris hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, alkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, carboxamido or mono- or di-alkylcarbamoyl. R%is hydrogen (provided that n is 0), alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, amino, monsubstituted amino, disubstituted amino, or hydroxyalkyl. Representative examples include, for example, 2-methoxyethyl, benzyloxymethyl, thiophen-2- © ylthiomethyl, 2-hydroxyethyl, and 2,3-dihydroxypropyl. “Heteroalkylene” means a linear saturated divalent hydrocarbon radical of one to six carbons or a branched saturated hydrocarbon radical of three to six carbon atoms with one, two or three substituents independently selected from -OR?, -NRR’, and -S(0),R? (where n is an integer from 0 to 2 ) where, R®, Rb, Rc, and Rare as defined herein for a heteroalkyl radical. Examples include, 2-hydroxyethan-1,1-diyl, ) 2-hydroxypropan-1,1-diyl and the like. “Heterosubstituted cycloalkyl” means a cycloalkyl group wherein one, two, or three hydrogen atoms are replaced by substituents independently selected from the group consisting of hydroxy, alkoxy, amino, monsubstituted amino, disubstituted amino, or —-SO,R (where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocydylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, amino, monsubstituted amino, disubstituted amino, or hydroxyalkyl). Examples include 4-hydroxycyclohexyl, 2-amino- cyclohexyl, “Heteroalkylsubstituted cycloalkyl” means a cycloalkyl group wherein one, two, or three hydrogen atoms are replaced independently by heteroalkyl groups.

Examples include 1-hydroxymethyl-cyclopent-1-yl, 2-hydroxymethyl-cyclohex-2-yl and the like. "Leaving group" has the meaning conventionally associated with it in synthetic organic chemistry i.e., an atom or group capable of being displaced by a nucleophile and includes halo (such as chloro, bromo, iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g. acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy), methoxy,

N,O-dimethylhydroxylamino, and the like. "Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient. "Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, . 15 hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentane- propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid, 4- toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1- carboxylic acid, glucoheptonic acid, 4,4'-methylenebis- (3-hydroxy-2-ene-1- carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. "Pro-drugs" means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group in a compound of Formula (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like. “Protecting group” refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in T.W. Greene and P.G. Futs, Protective Groups in

Organic Chemistry, (Wiley, 2nd ed. 1991) and Harrison and Harrison et al,

Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons. 1971- 1996). Representative amino protecting groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), - trimethyl silyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro- ) veratryloxycarbonyl (NVOC) and the like. Representative hydroxy protecting groups include those where the hydroxy group is either acylated or alkylated such as benzyl and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers. "Treating" or "treatment" of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or 3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. "A therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

In one aspect, the present invention provides compounds represented by the formula: ~~ 3 (0

HN ~ NN “So

R R (D. wherein the subscript n is an integer of from 0 to 3;

R'is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl and aralkyl; each R? is independently selected from the group consisting of alkyl, halo, ) : heteroalkyl and vinyl; and

R’ is heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylcarbonyl, heterosubstituted cycloalkyl, heterosubstituted cycloalkylalkyl, heterosubstituted cycloalkylalkenyl, heterosubstituted cycloalkylalkynyl, heteroalkylsubstituted cycloalkyl, heterocyclyl, heterocyclylalkyl, arylheteroalkyl, heteroarylheteroalkyl, - (alkylene)-C(O)R* and -(heteroalkylene)-C(O)R?; wherein

R* is alkyl, haloalkyl, hydroxy, alkoxy, amino, monsubstituted amino, disubstituted amino, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and their pharmaceutically acceptable salts.

In formula (I), the symbol R' represents a hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, or aralkyl group.

bd

More preferably R' represents a hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, or aralkyl group.

In a further preferred embodiment, R' is hydrogen, alkyl, cycloalkyl, or aralkyl. More preferably R' is alkyl or cycloalkyl. In preferred embodiments of R! . being alkyl, R' is a branched alkyl group in which the carbon atom attached to the nitrogen atom is a tetrahedral carbon atom, preferably having 0 or 1 attached hydrogen atoms. More preferably, R' will be 2-propyl, cyclohexyl or 1-methyl- cyclohexyl, most preferably 2-methyl-2-propyl.

In formula I, the symbol R? represents alkyl, halo, heteroalkyl or vinyl. R’can be attached to the phenyl ring at any of the remaining five valences otherwise occupied by hydrogen. The subscript n is an integer of from 0 to 3, indicating that ) the phenyl ring is substituted by from zero to three R’ groups, preferably by 1 or 2 R? groups. For those embodiments in which two or three R® groups are present, each can be independent of the other(s). In a preferred embodiment of R? in compounds of formula (I), nis 1 or 2 and each R? is halo or alkyl, more preferably R’ is halo.

Further preferred are those embodiments in which -(R%), represents 2-halo or 2,6- dihalo, more preferably 2-chloro or 2,6-dichloro.

As mentioned above, the symbol R® represents heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylcarbonyl, heterosubstituted cycloalkyl, heterosubstituted cycloalkylalkyl, heterosubstituted cycloalkylalkenyl, heterosubstituted cycloalkyl- alkynyl, heteroalkylsubstituted cycloalkyl, heterocyclyl, heterocyclylalkyl, arylhetero- alkyl, heteroarylheteroalkyl, -(alkylene)-C(O)R™ or -(heteroalkylene)-C(O)R>; wherein R* represents alkyl, haloalkyl, hydroxy, alkoxy, amino, monsubstituted amino, disubstituted amino, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl.

In a preferred embodiment of R}in compounds of formula (I), R3 is selected from heteroalkyl, heterocyclyl and heterosubstituted cycloalkyl. In one group of particularly preferred R’ embodiments, R is heteroalkyl, more preferably hydroxyalkyl or alkoxyalkyl. Particular hydroxyalkyl and alkoxyalkyl groups are 2- methoxyethyl, 2-hydroxyethyl, 1-hydroxy-2-propyl, 2-hydroxy-1-propyl, 1-hydroxy- 2-(hydroxymethyl)-3-propyl, 1,3-dihydroxy-2-propyl, 1,3-dimethoxy-2-propyl, 1- methoxy-2-(methoxymethyl)-3-propyl, 3,4-dihydroxy-1-cyclopentyl. More particular 2,3-dihydroxy-1-propyl and 2-methoxyethyl.

In another group of particularly preferred R® embodiments, R? is hetero- cyclylalkyl. Particular heterocyclylalkyl groups include 2-(N-piperidinyl)ethyl or 2- (N-(2-pyrrolidinonyl))ethyl.

In yet another group of particularly preferred embodiments, R? is -(alkylene)-

C(O)R*; wherein R* is hydroxy, amino, methylamino, dimethylamino, methyl, and ethyl. More preferably the alkylene portion is methylene, ethylene or propylene. : 15

In addition to the compounds described above, the present invention includes all pharmaceutically acceptable salts of those compounds along with prodrug forms of the compounds and all isomers whether in a pure chiral form or a racemic mixture or other form of mixture.

Still further, combinations of the preferred groups described above for compounds of formula (I) will form other preferred embodiments. In one group of particularly preferred embodiments R! is alkyl or cycloalkyl, R? is halo, R’ is hetero- alkyl or -(alkylene)-C(O)R*'; and n is 1 or 2. In another groups R' is alkyl or cyclo- alkyl, R? is halo, R’ is heteroalkyl and n is 1 or 2; or R! is alkyl or cycloalkyl, R? is halo,

R® is heterocyclyl and nis 1 or 2; or R' is alkyl or cycloalkyl, R? is halo, R’ is hetero- substituted cycloalkyl and n is 1 or 2 or R! is isopropyl, R? is halo and nis 1 or 2.

In particular, a compound of formula (I) is selected from the group consisting of 3-(2-chloro-phenyl)- 1-ethoxycarbonylmethyl-7-isopropylamino-3,4-dihydro- pyrimido{4,5-d]pyrimidin-2(1H)-one,

w 3-(2-chloro-phenyl)-1-carboxymethyl-7-isopropylamino-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-chloro-phenyl)-1-(2-methoxyethyl)-7-isopropylamino-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-chloro-phenyl)-7-isopropylamino-1-(2-methylsulfonylethyl)-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-chloro-phenyl)-1-(2-hydroxyethyl)-7-isopropylamino-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one, ’ 3-(2-chlorophenyl)-1-[(25)-2,3-dihydroxyethyl}-7-isopropylamino-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-chlorophenyl)-1-[(2R)-2,3-dihydroxyethyl}-7-isopropylamino-3,4- . dihydro-pyrimido(4,5-d}pyrimidin-2(1H)-one, and 7-isopropylamino-3-(2-chlorophenyl)-1-(2-piperidinyl-ethyl)-3,4-dihydro- pyrimido- {4,5-d]pyrimidin-2(1H)-one; and the pharmaceutically acceptable salts thereof. .

In another aspect the present invention provides methods of preparing the compounds of formula (I) described above. Briefly, the methods involve either: (a) treating a compound of formula II re = (Rn

AN ip: pz

A vo

R’ (IT) wherein n, R? and R® have the meanings provided with reference to formula I above, with the proviso that any interfering reactive group present is optionally in protected form, and L is a leaving group, with an amine of formula III

R'-NH, (III) wherein R' has the meaning provided with reference to formula I above,

with the proviso that any interfering reactive group present is optionally in protected form, and where required, deprotecting any protected reactive groups, or (b) treating a compound of formula IV

Z | 2

NN ——(R )n

XXX

=

HN N N oO

R' H (iv) wherein R', n, and R? have the meanings provided for formula I, with the proviso that any interfering reactive group present is optionally in protected form, with an alkylating agent of formula V

R>-X (V) wherein R? has the meaning provided with reference to formula I, and X is a leaving group or a hydroxy group that is activated during the reaction, with the proviso that any interfering reactive group present is optionally in protected form, and where required, deprotecting any protected reactive groups, and optionally converting a compound of formula I into a pharmaceutically acceptable salt.

The compounds of the present invention can be prepared by a variety of methods, using procedures well-known to those of skill in the art. For example, in one embodiment, the compounds are prepared using methods similar to those outlined in Scheme 1.

Scheme 1

Ss jos -_

Z R.

Rugg Cl S N INH la ib R°

CH

007 — JO

R. = =

S N NH Rg N NH 3 a BR ie R = = x Ie Rn IQ oC [cas TS

De n

R. R. — oN NH Ss” NT NH

Ia 3 x

R R le If

Ce el =—(R In = (R n ore ore

R. ~ -~— R. Z

SC ON ONT o s7NTNT0

O @] RS R°

Ih NN ig

Ce —— (Rn ore 2

HN N EN by 14 } R R

Treatment of a compound of formula Ia with a primary amine (R*-NH;) provides a compound of formula Ib. This reaction is conveniently carried outin a solvent which is inert under the reaction conditions, preferably an open-chain or cyclic ether (such as tetrahydrofuran), a halogenated aliphatic hydrocarbon, especially dichloromethane, an optionally halogenated aromatic hydrocarbon, a formamide or a lower alkanol. Suitably, the reaction is carried out at about -20°C to about 120°C.

Reduction of a compound of formula Ib provides an alcohol of formula Ic.

This reduction is typically carried out using lithium aluminium hydride in a manner well known to those of skill in the art (e.g. in a solvent which is inert under the conditions of the reduction, preferably an open-chain or cyclic ether, especially tetrahydrofuran, at about -200 C to about 70°C, preferably at about 0°C to about room temperature).

Oxidation of an alcohol of formula Ic in the next step provides a carboxaldehyde of formula Id. The oxidation is typically carried out with manganese dioxide, although numerous other methods can also be employed (see, for example,

ADVANCED ORGANIC CHEMISTRY, 4" ED., March, John Wiley & Sons, New York (1992)). Depending on the oxidating agent employed, the reaction is carried out conveniently in a solvent which is inert under the specific oxidation conditions, preferably a halogenated aliphatic hydrocarbon, especially dichloromethane, or an optionally halogenated aromatic hydrocarbon. Suitably, the oxidation is carried out at about 0°C to about 60°C.

Reaction of a carboxaldehyde of formula Id with a substituted aniline to provide a compound of formula Ie. This reaction may be carried out in the presence of an acid, e.g. an aromatic sulfonic acid, preferably 4-toluenesulfonic acid, with azeotropic removal of the water formed during the reaction. Conveniently, the reaction is carried out in a solvent which is inert under the reaction conditions, preferably an aromatic hydrocarbon, especially toluene, or an optionally halogenated aromatic hydrocarbon, and at a temperature of about 70°C to about 150°C, especially at the reflux temperature of the solvent to assist in the noted azeotropic removal of water.

Reduction of a compound of formula Ie to give a compound of formula If can be carried out using, for example, sodium borohydride, lithium aluminium hydride or sodium triacetoxyborohydride under conditions well known to those of skill in the art. Preferably, the compound of formula Ie is not purified, but rather the reaction mixture in which it is prepared is concentrated and the concentrate obtained is taken up in a solvent which is inert under the conditions of the reduction, preferably an open-chain or cyclic ether, especially tetrahydrofuran or an optionally halogenated aromatic hydrocarbon or a lower alkanol, and then treated with an aforementioned reducing agents. The reduction is suitably carried out at about 0° C to about 100°C, preferably at about 0-25°C.

Cyclization of a compound of formula If provides a bicyclic nitrogen heterocycle of formula Ig. The cyclization can be effected by reaction of If with } phosgene or trichloromethyl chloroformate (or phosgene equivalent), conveniently in the presence of a tertiary organic base, preferably a tri(lower alkyl)amine, especially triethylamine. More particularly, the cyclization is carried out in a solvent which is inert under the conditions of the reaction, preferably an open-chain or cyclic ether, especially tetrahydrofuran, an optionally halogenated aromatic hydrocarbon or a halogenated aliphatic hydrocarbon. Conveniently, the reaction is carried out at about -200C to about 50°C, preferably at about 0°C to about room temperature.

Oxidation of Ig with 3-chloroperbenzoic acid provides a sulfone (Ih) which can be converted to a variety of target compounds. Typically the oxidation of Ig is carried out in a solvent which is inert under the conditions of the oxidation, preferably a halogenated aliphatic hydrocarbon, especially chloroform or dichloromethane, and at about -20°C to about 50°C, preferably about 0°C to about room temperature.

«

Finally, treatment of Th with an amine (R'-NH_) provides the target compounds of formula I. The reaction can be carried out in the presence or absence of solvent. Conveniently, the reaction is carried out at temperatures of from about 00°C to about 200°C, more preferably about room temperature to about 150°C.

Accordingly, the present invention provides a method of preparing compounds of formula I, by treating a compound of general formula Ii with an amine (R'-NH). = (Rn a2 (Rh

SH Ise ~ J —— ~~

AN No HN” ON So

Re ty =X) li I

In compound Ii, the symbols R?, R® and the subscript n have the meanings provided above with reference to formula I. The letter L represents a leaving group which can be a halogen, a lower alkanesulfonyl group (e.g., methanesulfonyl or trifluoromethanesulfonyl) or an aromatic sulfonyl group (e.g, benzenesulfonyl or 4- toluenesulfonyl). Other suitable leaving groups are known to those of skill in the art and can be found in, for example, ADVANCED ORGANIC CHEMISTRY, 4™ ED., March,

John Wiley & Sons, New York (1992). Suitable amines ( R!-NH,) are those in which

R' represents any of the R' groups noted for formula I.

In a preferred embodiment, the bicyclic nitrogen heterocycle can be constructed and R’ can be introduced at a later stage of synthesis as shown in Scheme

»

Scheme 2

J ¢ 2

XN (RY), jonas Cr n

R« —~ — Ru. =

S N° NH, s N vo

H lla lib je ye = Rn «(Rs

Poa sy ~ ——— R N yp

Regn No s”ON No do bs

R [= : lid AN lic

Je ~~ (Rn

Isa

Z

HN" 'N So b x:

R R

1

Compound IIa, the starting material in Scheme 2, can be prepared from commercially available ethyl 4-amino-2-mercapto-pyrimidine-5-carboxylate. Briefly, treatment of the mercapto compound with a suitable alkylating agent (R-X) provides a compound of formula Ib (R® =H). Conversion of Ib (R®> = H) to Ila can follow the steps provided in Scheme I.

Cyclization of IIa provides a bicyclic nitrogen heterocycle of formula IIb. The cyclization can be effected by reaction of Ila with phosgene or trichloromethyl

Claims (16)

Claims

1. A compound selected from the group of compounds represented by formula I: = ea C0 ve N" NS 0 R R® M wherein the subscript n is an integer of from 0 to 3; R! is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl and aralkyl; each R? is independently selected from the group consisting of alkyl, halo, heteroalkyl and vinyl; and R’ is heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylcarbonyl, heterosubstituted cycloalkyl, heterosubstituted cycloalkylalkyl, heterosubstituted cycloalkylalkenyl, heterosubstituted cycloalkylalkynyl, heteroalkylsubstituted cycloalkyl, heterocyclyl, heterocyclylalkyl, arylheteroalkyl, heteroarylheteroalkyl, - (alkylene)-C(O)R* and -(heteroalkylene)-C(O)R*; wherein R* is alkyl, haloalkyl, hydroxy, alkoxy, amino, monsubstituted amino, disubstituted amino, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and their pharmaceutically acceptable salts.

2. A compound in accordance with claim 1, wherein R! is a member selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl and aralkyl.

3. A compound in accordance with claim 1, wherein R' is a member selected from the group consisting of hydrogen, alkyl, cycloalkyl and aralkyl.

4. A compound in accordance with claim 3, wherein R' is alkyl.

5. A compound in accordance with claim 3, wherein R' is cycloalkyl.

6. A compound in accordance with claim 1, wherein n is an integer of from 1 to 2, and each R? is independently selected from the group consisting of halo and alkyl.

7. A compound in accordance with claim 6, wherein n is an integer of from 1 to 2, and each R? is independently a halogen.

8. A compound in accordance with claim 7, wherein -(RH), represents 2-halo or 2,6-dihalo.

9. A compound in accordance with claim 1, wherein R? is heteroalkyl.

10. A compound in accordance with claim 1, wherein R? is heterocyclylalkyl.

11. A compound in accordance with claim 7, wherein R' is alkyl or cycloalkyl, R’ is halo, R? is heteroalkyl and n is 1 or 2.

12. A compound in accordance with claim 7, wherein R' is alkyl or cycloalkyl, R? is halo, R® is heterocyclyl and n is 1 or 2.

13. A compound in accordance with claim 7, wherein R' is alkyl or cycloalkyl, R? is halo, R? is heterosubstituted cycloalkyl and n is 1 or 2.

14. A compound in accordance with claim 1, wherein R! is isopropyl, R? is halo and nis 1or2.

15. A compound according to claim 1 selected from the group consisting of 3-(2-chloro-phenyl)-1-ethoxycarbonylmethyl-7-isopropylamino- 3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-chloro-phenyl)-1-carboxymethyl-7-isopropylamino-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one,

3-(2-chloro-phenyl)-1-(2-methoxyethyl)-7-isopropylamino-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-chloro-phenyl)-7-isopropylamino- 1-(2-methylsulfonylethyl)-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-chloro-phenyl)-1-(2-hydroxyethyl)-7-isopropylamino-3,4-dihydro- pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-chlorophenyl)-1-[(2S)-2,3-dihydroxyethyl]-7-isopropylamino-3,4- dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, 3-(2-chlorophenyl)-1-[(2R)-2,3-dihydroxyethyl]- 7-isopropylamino-3,4- dihydro-pyrimido([4,5-d]pyrimidin-2(1H)-one, and 7-isopropylamino-3-(2-chlorophenyl)- 1-(2-piperidinyl-ethyl)-3,4-dihydro- pyrimido-[4,5-d]pyrimidin-2(1H)-one; and the pharmaceutically acceptable salts thereof. :

16. A method for the preparation of a compound of claim 1, said method comprising: (a) treating a compound of formula II Le oo” A N No R’ (I wherein n, R? and R’ have the meanings provided in claim 1, with the proviso that any interfering reactive group present is optionally in protected form, and L is a leaving group, with an amine of formula III R'-NH, (III) wherein R! has the meaning provided in claim 1, with the proviso that any interfering reactive group present is optionally in protected form, and where required, deprotecting the protected reactive group present in the reaction product, and optionally converting a compound of formula I into a pharmaceutically acceptable salt.

.-»

17. A pharmaceutical composition comprising a compound according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, and a compatible pharmaceutical carrier.

18. A compound according to any one of claims 1-15 for use as a therapeutic agent.

19. A compound according to any one of claims 1-15 for use as a therapeutic agent in the treatment or prophylaxis of a p38 mediated disorder.

20. A compound according to any one of claims 1-15 for use in the treatment or prophylaxis of arthritis, Crohns disease, irritable bowel syndrome adult respiratory distress syndrome and chronic obstructive pulmonary disease.

21. The use of a compound according to any one of claims 1-15 in the treatment or prophylaxis of a p38 mediated disorder, especially in the treatment or prophylaxis of arthritis, Crohns disease, irritable bowel syndrome adult respiratory distress syndrome and chronic obstructive pulmonary disease.

22. A process for the preparation of a pharmaceutical preparation comprising bringing one or more compounds according to any one of claims 1-15, or a salt thereof, and, if desired, one or more other therapeutically valuable substance into a galenical administration form together with a compatible pharmaceutical carrier.

23. The use of a compound according to any one of claims 1-15 in the preparation of a pharmaceutical composition for the treatment or prophylaxis of arthritis, Crohns disease, irritable bowel syndrome adult respiratory distress syndrome and chronic obstructive pulmonary disease.

24. A compound according to claim 1 whenever prepared according to a process according to claim 16.

54 PCT/EP00/10077

25. A substance or composition for use in a method for the treatment or prophylaxis of arthritis, Crohns disease, irritable bowel syndrome, adult respiratory distress syndrome and chronic obstructive pulmonary disease, said substance or composition comprising a compound according to any one of claims 1-15, and said method comprising administering said substance or composition.

26. The invention substantially as hereinbefore described, especially with references to the new compounds, processes, pharmaceutical preparations and uses thereof.

27. A compound according to claim 1, substantially as herein described and illustrated.

28. A method according to claim 16, substantially as herein described and illustrated.

29. A composition according to claim 17, substantially as herein described and illustrated.

30. Use according to claim 21 or claim 23, substantially as herein described and illustrated.

31. A process according to claim 22, substantially as herein described and illustrated.

32. A substance or composition for use in a method of treatment or prophylaxis according to claim 25, substantially as herein described and illustrated.

33. A new compound; a new method for the preparation of a compound; a new composition; a new use of a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof; a mew process for the preparation of a preparation; or a AMENDED SHEET

55 PCT/EP00/10077 substance or composition for a new use in a method of treatment or prophylaxis, substantially as herein described.

AMENDED SHEET